The present invention relates to a method of treating neurological and mental disorders which are associated with and/or related pathogenetically to deficient serotonin neurotransmission and impaired pineal melatonin functions in humans.
The pineal gland is a magnetosensor organ in the brain of humans and other mammals and its stimulation with an AC pulsed magnetic field has shown beneficial effects in the treatment of neurological and mental disorders which are associated with or related pathogenetically to impairment of pineal melatonin functions including multiple sclerosis, Parkinson's disease, dystonia, tardive dyskinesia, epilepsy, migraine, Alzheimer's disease, depression (including seasonal affective disorder), and schizophrenia.
For many years physiologists considered the pineal gland, lodged deep within the brain, a vestigial organ which is merely an anatomical remnant of a primary sensory system. To the clinician the pineal gland, by virtue of its midline position and calcification, was of interest as a radiological landmark to identify intracranial space occupying processes. The pineal gland attracted scientific attention in 1963, when its primary secretion, melatonin, was first recognized as a hormone. Wurtman and Axelrod (1965) "The pineal gland." Scientific American, 231, 50-60) termed the pineal gland a "neuroendocrine transducer," an organ which converts neural signals from the external environment such as photic, acoustic, thermic, and magnetic cues into neuroendocrine output which acts on the nervous system largely via the secretion of its principal hormone melatonin. The pineal gland is unique among endocrine organs for a number of reasons: (1) it is one of the few unpaired endocrine organs; (2) on a weight basis, it receives one of the richest blood supplies of any organ; (3) it lies outside the blood brain barrier, but has direct access to the cerebrospinal fluid (CSF) via the third ventricle; (4) it produces and/or contains high concentrations of a number of different indoleamines and low molecular weight peptides of probable endocrine importance; and (5) it is responsive to changes in magnetic field strength and to external electrical stimuli (Foley et al., (1986) "Pineal indoles: significance and measurement." Neuroscience & Biobehavioral Reviews, 10, 273-293).
Over the past several years scientists have come to suspect that melatonin is a "master hormone" involved in the control of circadian rhythms (biological cycles that recur at approximately 24-hour intervals), and protecting against some of the common diseases of aging. Melatonin is now recognized to exert an important influence on a host of biological functions including synchronization of biological rhythms, stabilization of neuronal activity, regulation of sexual maturation and reproduction, immunomodulation, temperature control, sleep, mood, pain control, cognitive functions, and motor behavior (Ehrlich and Apuzzo (1985) "The pineal gland: anatomy, physiology, and clinical significance." Journal of Neurosurgery, 63, 321-341; Miles and Philbrick (1988) "Melatonin and Psychiatry." Biological Psychiatry, 23, 405-425; Romijn (1978). "The pineal, a tranquillizing organ?" Life Sciences, 23, 2257-2274; Lakin et al., (1981) "Involvement of the pineal gland and melatonin in murine analgesia." Life sciences, 29, 2543-2551; Kavaliers et al., (1983) "Ageing, opioid analgesia and the pineal gland." Life Sciences, 32, 2279-2287; Cotzias et al., (1971) "Melatonin and abnormal movement induced by L-dopa in mice." Science, 173, 450-452; Reiter (1991) "Pineal melatonin: cell biology of its synthesis and of its physiological interactions." Endocrine Reviews, 12, 151-180).
Many of the biological effects of melatonin result from its action on serotonergic neurons indicating that the neurotransmitter serotonin is an important mediator of melatonin's action (Anton-Tay et al., (1968) "Brain serotonin concentration: elevation following intraperitoneal administration of melatonin." Science, 162, 277-278; Gaffori and Van Ree (1985) "Serotonin and antidepressant drugs antagonize melatonin-induced behavioral changes after injection into the nucleus accumbens of rats." Neuropharmacology, 24, 237-244; Namboodiri et al., (1983) "5-hydroxytryptophan elevates serum melatonin." Science, 221, 659-661; Aldegunde et al., (1985) "Effects of pinealectomy on regional brain serotonin metabolism." International Journal of Neuroscience, 26, 9-13; Sugden and Morris (1979) "Changes in regional brain levels of tryptophan, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, dopamine and noradrenaline after pinealectomy in the rat." Journal of Neurochemistry, 32, 1593-1594; Olcese (1985) "Enhancement of melatonin's antigonadal action by daily injections of the serotonin uptake inhibitor fluoxetine in male hamsters." Journal of Neural Transmission, 64, 151-161; Smythe and Lazarus (1974) "Growth hormone responses to melatonin in man." Science, 184, 1373; Koulu and Lammintausta (1979) "Effect of melatonin on L-tryptophan and apomorphine-stimulated growth hormone secretion in man." Journal of Clinical Endocrinology & Metabolism, 49, 70-72).
Melatonin secretion has been shown to change across the lifespan, peaking in childhood and gradually decreasing after puberty. The gradual decline in the secretory activity of the pineal gland after puberty has generally been linked with the process of aging as melatonin is thought to counteract the deleterious effects of oxygen free radicals--unstable molecules thought to play an important part in atherosclerosis and other diseases associated with aging (Nair et al., (1986) "Plasma melatonin--an index of brain aging in humans?" Biological Psychiatry, 21, 141-150; Sack et al., (1986) "Human melatonin production decreases with age." Journal of Pineal Research, 3, 379-388; Armstrong and Redman (1991) "Melatonin: a chronobiotic with antiaging properties?" Medical Hypotheses, 34, 300-309).
Impaired pineal melatonin functions have been implicated in the pathophysiology of numerous systemic, neurological and mental disorders including cancer, autoimmune disorders (i.e., rheumatoid arthritis, systemic lupus), diabetes mellitus, hypercholesterolemia, mental depression including seasonal affective disorder (SAD), schizophrenia, Parkinson's disease, Alzheimer's disease, Korsakoff's dementia, tardive dyskinesia, epilepsy, narcolepsy, migraine, and multiple sclerosis. These diseases are associated either with deficient melatonin production and/or disruption of circadian melatonin secretion, as disclosed in Anton-Tay et al., (1971) "On the effects of melatonin upon human brain. Its possible therapeutic implications." Life sciences, 10, 841-850; Smith et al., (1978) "Decrease in human serum melatonin concentrations with age." Journal of Neural Transmission, 13 (Suppl), 396; Pavel et al., (1980) "Vasotocin, melatonin and narcolepsy: possible involvement of the pineal gland in its patho-physiological mechanism." Peptides, 1, 281-284; Martin et al., (1984) "Decreased 6-hydroxymelatonin excretion in Korsakoff's psychosis." Neurology, 34, 966-968; Fanget et al., (1989) "Nocturnal plasma melatonin levels in schizophrenic patients." Biological Psychiatry, 25, 499-501; Skene et al., (1990) "Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of age and Alzheimer's disease." Brain Research, 528, 170-174; Souetre et al., (1989) "Abnormal melatonin response to 5-methoxypsoralen in dementia." American Journal of Psychiatry, 146, 1037-1040; Renfrew et al., (1987) "Circadian rhythms in Alzheimer's disease." Neurosciences Abstracts, 1, 322; Armstrong and Redman (1991) "Melatonin: a chronobiotic with antiaging properties?" Medical Hypotheses, 34, 300-309; Nair et al., (1986) "Plasma melatonin--an index of brain aging in humans?" Biological Psychiatry, 21, 141-150; Tohgi et al., (1992) "Concentrations of serotonin and its related substances in the cerebrospinal fluid in patients with Alzheimer-type dementia." Neuroscience Letters, 141, 9-12; Fertl et al., (1991) "Circadian secretion pattern of melatonin in Parkinson's disease." Journal of Neural Transmission, 3, 41-47; Fertl et al., (1993) "Circadian secretion pattern of melatonin in de novo Parkinsonian patients: evidence for phase-shifting properties of 1-dopa." Journal of Neural Transmission (P-D Sect), 5, 227-234; Sandyk (1992) "The pineal gland and the clinical course of multiple sclerosis." International Journal of Neuroscience, 62, 65-74; Sandyk (1992) "The pineal gland and multiple sclerosis." (Editorial) International Journal of Neuroscience, 63, 206-215; Sandyk and Awerbuch (1993) "Nocturnal melatonin secretion in multiple sclerosis patients with affective disorders." International Journal of Neuroscience, 68, 227-240; Toglia (1986) "Is migraine due to a deficiency of pineal melatonin?" Italian Journal of Neurological Sciences, 7, 319-32; Sandyk and Kay (1990) "Pineal melatonin in schizophrenia: a review and hypothesis." Schizophrenia Bulletin, 16, 653-662; Sandyk et al., (1990) "Pineal gland calcification and tardive dyskinesia." Lancet, 335, 1528; Robinson et al., (1991) "Serum melatonin levels in schizophrenic and schizoaffective hospitalized patients." Acta Psychiatrica Scandinavica, 84, 221-224; Miles and Philbrick (1988) "Melatonin and Psychiatry." Biological Psychiatry, 23, 405-425; Nir et al., (1969) "Changes in the electrical activity of the brain following pinealectomy." Neuroendocrinology, 4, 122-127; Philo (1982) "Catecholamines and pinealectomy-induced convulsions in the gerbil (Meriones unguiculatus)." Progress in Clinical Biological Research, 92, 233-241; Reiter et al., (1973) "Nature and time course of seizures associated with surgical removal of the pineal gland from parathyroidectomized rats." Experimental Neurology, 38, 386-397).
The pineal gland is a neural structure that is functionally related to the visual system. The circadian production of melatonin is determined by the photoperiodic environment to which animals are exposed. Bright light suppresses pineal melatonin synthesis and secretion while ambient darkness stimulates the production and secretion of the hormone. The effects of the environmental illumination on the pineal gland are mediated via a well-delineated retino-hypothalamic-pineal circuit. The rhythms of melatonin secretion are generated by the paired suprachiasmatic nuclei (SCN) of the hypothalamus which serve as the body's biological clock. Serotonin concentrations are higher in the pineal than in any other organ or in any brain region. They exhibit a striking diurnal rhythm, remaining at a maximum level (in the rat) during the daylight hours and falling by more than 80% soon after the onset of darkness, as serotonin is converted to melatonin.
Melatonin is a unique indole derivative. It acts both as a neurotransmitter and neurohormone. Melatonin is lipid soluble and rapidly crosses the blood brain barrier and other tissues. Once released from the pineal gland, which is highly vascularized, it enters both the general circulation and the cerebrospinal fluid (CSF). Melatonin acts on the central and peripheral nervous system as well as on peripheral endocrine target tissues. Laboratory studies have indicated that the primary effect of melatonin is on the neuroendocrine system where it has been shown to influence the activity of the hypothalamic-pituitary-gonadal-thyroid-adrenal axis. In addition, melatonin has been shown to be involved in the regulation of the activity of monoaminergic neurotransmitters including serotonin, dopamine and norepinephrine as well as gamma-aminobutyric acid (GABA) and the opioid peptides as disclosed in (Ehrlich and Apuzzo (1985) "The pineal gland: anatomy, physiology, and clinical significance." Journal of Neurosurgery, 63, 321-341; Anton-Tay (1974) "Melatonin: effects on brain function." Advances in Biochemical Psychopharmacology, 11, 315-324; Datta and King (1980) "Melatonin: effects on brain and behavior." Neuroscience & Biobehavioral Reviews, 4, 451-458; Rosenstein and Cardinali (1986) "Melatonin increases in vivo GABA accumulation in rat hypothalamus, cerebellum, cerebral cortex and pineal gland." Brain Research, 398, 403-406; Zisapel et al., (1982) "Inhibition of dopamine release by melatonin: regional distribution in the rat brain." Brain Research, 246, 161-163). At a cellular level, melatonin acts to produce antioxidants as by increasing cGMP. It also provides guanine nucleotides for DNA and partakes in DNA repair mechanisms and in maintenance of membranes and other intracellular components (Grad and Rozencwaig (1993) "The role of melatonin and serotonin in aging: update." Psychoneuroendocrinology, 18, 283-295).
In addition to the ambient light/dark cycle, the activity of the pineal gland and hence the rate of melatonin secretion is influenced also by the earth's geomagnetic field which is in the order of 30,000-60,000 nanotesla (0.3-0.6 Gauss). The earth's magnetic field is primarily a nontime-varying (DC) field with angle of incidence to the earth's surface increasing with increasing latitude. For comparison, anthropogenic magnetic fields are primarily time varying at 50 or 60 Hz and harmonic of these frequencies. Typical magnetic fields measured in residential settings range from 0.1 microtesla to 3 microtesla at 60 Hz frequency. The geomagnetic field has been a part of the environment throughout the evolution of animals and is used by certain species in their adaptive strategies. Organisms are capable of perceiving its intensity, polarity, and direction (Gould (1984) "Magnetic field sensitivity in animals." Annual Review of Physiology, 46, 585-598). It is thought that the circadian rhythmicity of the earth's magnetic field may have an additional "Zeitgeber" (time cue) function in the organization of biological rhythms (Cremer-Bartels et al., (1984) "Magnetic field of the earth as additional zeitgeber for endogenous rhythms?" Naturwissenschaften, 71, 567-574; Wever (1968) "Einfluss Schwacher Elektro-magnetischer Felder auf die Circadiane Periodik des Menschen." Naturwissenschaften, 55, 29-32).
Since the activity of the pineal gland is sensitive to the influences of the geomagnetic field it has been suggested that it functions as a magnetoreceptor as well (Semm et al., (1980) "Effects of an earth-strength magnetic field on electrical activity of pineal cells." Nature, 288, 607-608; Semm (1983) "Neurobiological investigations on the magnetic sensitivity of the pineal gland in rodents and pigeons." Comparative Biochemistry and Physiology, 76A, 683-689; Olcese et al., (1988) "Geomagnetic field detection in rodents." Life Sciences, 42, 605-613; Demaine and Semm (1985) "The avian pineal gland as an independent magnetic sensor." Neuroscience Letters, 62, 119-122; Rudolph et al., (1988) "Static magnetic fields decrease nocturnal pineal cAMP in the rat." Brain Research, 446, 159-160). Based on histological studies and electrophysiological single unit recordings from the pineal gland of rodents and pigeons, it has been estimated that 20%-30% of pineal cells respond to magnetic fields (Semm (1983) " Neurobiological investigations on the magnetic sensitivity of the pineal gland in rodents and pigeons." Comparative Biochemistry and Physiology, 76A, 683-689). Electrophysiological studies by Reuss et al., (1983) "Different types of magnetically sensitive cells in the rat pineal gland" Neuroscience Letters, 40, 23-26 have demonstrated the presence of different types of magnetically sensitive cells in the pineal gland of the rat.
Furthermore, short-term exposure of experimental animals to magnetic fields of various intensities has been shown to alter temporarily the secretion of melatonin while more chronic exposure may even induce ultrastructural morphological changes in the pineal gland (Bardasano et al., (1985) "Ultrastructure of the pineal cells of the homing pigeon Columba livia and magnetic fields (first trials)." Journal Fuer Hirnforschung, 26, 471-475; Semm et al., (1980) "Effects of an earth-strength magnetic field on electrical activity of pineal cells." Nature, 288 607-608; Welker et al., (1983) "Effects of an artificial magnetic field on serotonin N-acetyltransferase activity and melatonin content of the rat pineal gland." Experimental Brain Research 50, 426-432; Wilson et al., (1981) "Neuroendocrine mediated effects of electromagnetic field exposure: possible role of the pineal gland." Life Sciences, 45, 1319-1332).
The human pineal gland, likewise, is believed to be sensitive to changes in the environmental magnetic fields. Howard et al., (1965) "Psychiatric ward behaviour and geophysical parameters." Nature, 205, 1050-1052 made the seminal observations of a relationship between increased geomagnetic activity and the rate of admission of patients to psychiatric facilities. Rajaram and Mitra (1981) "Correlation between convulsive seizure and geomagnetic activity." Neuroscience Letters, 24, 187-191 and Venkatraman (1976) "Epilepsy and solar activity. An hypothesis." Neurology (India), 24, 1-5 reported an association between changes in the geomagnetic field due to magnetic storms and frequency of seizures in epileptic patients. (Semm (1992) "Pineal function in mammals and birds is altered by earth-strength magnetic fields." In Moore-Ede, Campbell, and Reiter (Eds.), Electromagnetic Fields and Circadian Rhythmicity, (pp. 53-62), Birkhauser: Boston) observed in normal subjects placed in the center of a Helmholtz coil system that inversion of the horizontal component of the ambient magnetic field for 30 minutes at midnight resulted in a significant (70%) depression of plasma melatonin concentrations.
Melatonin is a "master hormone" involved in the regulation of a host of physiological functions related to the control of neuroendocrine functions, immunomodulation, analgesia, motor behavior, mood, sleep, cognition, and neurotransmitter synthesis and release (Datta and King (1980) "Melatonin: effects on brain and behavior." Neuroscience & Biobehavioral Reviews, 4, 451-458; Ehrlich and Apuzzo (1985) "The pineal gland: anatomy, physiology, and clinical significance." Journal of Neurosurgery, 63, 321-341; Frazer and Brown (1987) "Melatonin: a link between the environment and behavior."! Integrative Psychiatry, 5, 3-26; Bradbury et al., (1985) "Melatonin action in the midbrain can regulate forebrain dopamine function both behaviourally and biochemically." In Brown and Wainwright (Eds.), The Pineal Gland: Endocrine Aspects (pp. 327-332) New York: Pergamon Press). Consequently, it is believed that by influencing the activity of the pineal gland and melatonin production and resetting biological rhythms, pulsed magnetic fields may be used therapeutically.
The present inventor and others indicate that pulsed magnetic fields in the picotesla range intensity applied externally over the head are beneficial in the treatment of several neurological disorders including epilepsy, Parkinson's disease, dystonia, tardive dyskinesia, migraine, and multiple sclerosis (Anninos et al., (1991) "Magnetic stimulation in the treatment of partial seizures." International Journal Neuroscience, 60, 141-171; Sandyk and Anninos (1992) "Attenuation of epilepsy with application of external magnetic fields: a case report." International Journal of Neuroscience, 66, 75-85; Sandyk (1992) "The influence of the pineal gland on migraine and cluster headaches and the effects of treatment with picotesla magnetic fields." International Journal of Neuroscience, 67, 145-171; Sandyk (1992) "Weak magnetic fields as a novel therapeutic modality in Parkinson's disease." International Journal of Neuroscience, 66, 1-15; Sandyk (1992) "Successful treatment of multiple sclerosis with magnetic fields." International Journal of Neuroscience, 66, 237-250; Sandyk and Iacono (1993) "Resolution of longstanding symptoms of multiple sclerosis by application of picotesla range magnetic fields." International Journal of Neuroscience, 70, 255-269; Sandyk and Iacono (1993) "Reversal of visual neglect in Parkinson's disease by treatment with picotesla range magnetic fields." International Journal of Neuroscience, 73, 93-107).
However, the therapeutic efficacy of externally applied magnetic fields, as administered in the prior art without the use of any pharmacological-nutritional composition, is believed by the inventor to be limited by several factors:
First, the pineal gland tends to undergo calcification with progression of age and particularly in association with various disease states (Trentini et al., (1987) "Pineal calcification in different physiopathological conditions in humans." In Trentini et al., Fundamentals and clinics in pineal research, (pp. 291-304), New York: Raven Press; Welsh (1985) "Pineal calcification: structural and functional aspects." Pineal Research Reviews, 3, 41-68; Zimmerman and Bilaniuk (1982) "Age-related incidence of pineal calcification detected by computed tomography." Radiology, 142, 659-662; Sandyk et al., (1990) "Pineal gland calcification and tardive dyskinesia." Lancet, 335, 1528; Sandyk et al., (1991) "Pineal calcification and anticonvulsant responsiveness to artificial magnetic stimulation in epileptic patients." International Journal of Neuroscience, 60, 173-175; Sandyk and Awerbuch (1991) "The pineal gland in multiple sclerosis." International Journal of Neuroscience, 61, 61-67. For instance, in the case of epileptic patients it has been found that patients who demonstrated calcification of the pineal gland on computed tomography (CT) scan responded less favourably to magnetic treatment in terms of seizure control than those subjects who showed no calcification of the pineal gland (Sandyk et al., (1991) "Pineal calcification and anticonvulsant responsiveness to artificial magnetic stimulation in epileptic patients." International Journal of Neuroscience 60, 173-175).
Second, the secretory activity of the pineal gland, as reflected by nocturnal melatonin plasma levels, diminishes with age. In addition, aging is associated with diminished capacity of the pineal gland to initiate the production of melatonin after sunset (Nair et al., (1986) "Plasma melatonin--an index of brain aging in humans?" Biological Psychiatry, 21, 141-150; Sack et al., (1986) "Human melatonin production decreases with age." Journal of Pineal Research, 3, 379-388). The decline in the secretory activity of the pineal gland with aging reflects in part the limited regenerative abilities of the pineal cells due to their neuronal derivation.
Finally, melatonin secretion is significantly decreased or its circadian rhythmicity is disrupted in various neurological and mental disorders including multiple sclerosis, Parkinson's disease, Alzheimer's disease, Korsakoff's dementia, depression, and schizophrenia (Martin et al., (1984) "Decreased 6-hydroxymelatonin excretion in Korsakoff's psychosis." Neurology, 34, 966-968; Skene et al., (1990) "Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of agen and Alzheimer's disease." Brain Research, 528, 170-174; Nair et al. (1986) "Plasma melatonin rhythm in normal aging and Alzheimer's disease." Journal of Neural Transmission, 21 (suppl), 494; Sandyk and Awerbuch (1992) "Nocturnal melatonin secretion in multiple sclerosis patients with affective disorders." International Journal of Neuroscience, 68, 227-240; Miles and Philbrick (1988) "Melatonin and psychiatry." Biological Psychiatry, 23, 405-425; Fertl et al., (1993) "Circadian secretion pattern of melatonin in de novo Parkinsonian patients: evidence for phase-shifting properties of 1-dopa." Journal of Neural Transmission, (P-D Sect), 5, 227-234).
It is believed that reduction in the activity of the pineal gland in these neurological and mental disorders may be related to various factors including, among others, decrease in pineal receptor sensitivity and/or density, decline in the availability of nutritional co-factors for serotonin and subsequent melatonin synthesis, decline in the capacity of pineal cells to synthesize serotonin from tryptophan, decrease in sympathetic nervous system activity which provides a stimulus for melatonin synthesis, and progressive loss of neurons in the suprachiasmatic nucleus of the hypothalamus which activate the pineal gland.
Thus, a definite need exists in therapy today for an effective treatment for patients with neurological and mental disorders which are associated with and/or related pathogenetically to deficient serotonin neurotransmission and impaired pineal melatonin functions.